Fatty Liver Disease (FLD) is a leading public health problem in the U.S. and elsewhere. Liver parenchymal cells (hepatocytes) play an essential role in regulating glucose and fat homeostasis which is believed to be achieved by the proper action of the Insulin-Insulin Receptor (I-IR) axis. Dysregulation of this pathway in Type 2 Diabetes (T2D) can result in non-alcoholic FLD (NAFLD) - a disorder showing a spectrum of pathologies from hepatocyte fat accumulation (steatosis), inflammation and necrosis of steatotic hepatocytes (NASH), fibrosis, cirrhosis and liver cancer that are not well understood at the molecular level. Hepatic insulin resistance is believed to be a driver of this process and results from lack of optimum insulin receptor (IR) function in hepatocytes. Recently, we established that the Hepatocyte Growth Factor (HGF)-MET signaling axis controls hepatic glucose and fat metabolism and is essential for optimum hepatic insulin response. Given the fact that the HGF-MET signaling axis not only controls metabolism but also modulates cell growth and survival (i.e. suppression of cell death), we propose that diminished HGF-MET signalling (that is, HGF Resistance) in the liver acts as a double-edged sword causing a vicious cycle of hepatocyte metabolic derangement coupled with an inability to overcome (or survive) liver damage provoked by insults such as lipotoxicity. RIPK1 (Receptor Interacting Protein Kinase 1) has emerged as the master switch that dictates inflammation and necrosis. Based on our groundbreaking preliminary data examining the impact of the HGF- MET axis on RIPK1 in hepatocytes, we hypothesize that, under normal conditions in hepatocytes, the HGF-MET axis negatively regulates RIPK1 enzymatic activity through directly tyrosine phosphorylating RIPK1 promoting RIPK1 proteosomal degradation in order to protect hepatocytes from RIPK1's pro- inflammatory and pro-necrotic actions, and that, in the setting of hepatocyte lipotoxicity and NAFLD, reduced and defective HGF-MET signaling results in escape of RIPK1 from HGF-MET-mediated negative regulation unleashing RIPK1-dependent hepatocyte inflammation and necrotic cell death. We propose that restoration of HGF-MET signaling will negate this effect. We outline three specific aims to test this novel hypothesis. Aim 1 - we will investigate the functional consequences of tyrosine phoshorylation of RIPK1 by MET using site directed mutagenesis and in vitro hepatocytic cell cuture systems to establish that this modification results in inhibition of RIPK1 enzymatic activity and promotes its proteosomal degradation - hence, RIPK1 mediated inflammation and necrosis are prevented. We will also test the hypothesis that disruption of MET signaling results in uncontrolled RIPK1 activity unleashing RIPK1- mediated hepatocyte death. The molecular mechanisms that regulate RIPK1 are not well understood. We have discovered that MET directly tyrosine phosphorylates RIPK1 on Tyr384 downregulating RIPK1 kinase activity and marking it for proteosomal degradation. Thus, studies under this aim will decipher the molecular regulation of RIPK1 by the tyrosine kinase growth factor receptor MET. Aim 2 - we will directly test our hypothesis that HGF-MET mediated regulation of RIPK1 has biological and pathological implications to liver homeostasis in the setting of fatty liver disease using loss- and gain-of-function mouse models. We believe that HGF-MET insufficiency caused by lipotoxicity exacerbates RIPK1-induced liver inflammation and necrosis and that restoration of HGF-MET signaling will negate this effect. We have discovered that RIPK1 is upregulated and HGF/MET are downregulated in human and mouse fatty liver. The molecular mechanisms that drive progression of fatty liver disease are not well understood. We propose that reduced HGF/MET signaling in fatty hepatocytes causes RIPK1 to escape MET-mediated negative regulation driving RIPK1-induced hepatocyte necrosis. We will induce fatty liver disease (by feeding a high fat diet) in liver specific loss-of function (using LMETKO and LRIPK1 KO) and gain- of-function (Albumin-HGF Transgenic) mouse models. Aim 3 - we will determine the molecular basis of RIPK1 upregulation in hepatocytes by lipotoxicity. We hypothesize that any defect in HGF/MET signaling provoked by lipotoxicity will promote RIPK1 accumulation. Liptoxicity may also stabilizes RIPK1 via direct inhibition of the proteasome. We will perform a series of comprehensive experiments using a hepatocyte culture system and in vivo models to test if one or both of these pathways are active to define the molecular bases of RIPK1 dysregulation in fatty liver disease. The proposed studies will establish a new paradigm by which tyrosine kinase growth factor receptor systems like HGF-Met prevent hepatic inflammation and necrosis by downmodulating the pro-inflammatory and pro- death activity of RIPK1. Our studies will provide rationale for manipulating these key mediators (HGF-MET and RIPK1) in the clinical setting of inflammatory hepatic conditions such as NASH or alcoholic hepatitis.